t0901317 and Multiple-Sclerosis

Multiple sclerosis is a chronic, inflammatory, demyelinating disease of the central nervous system in which macrophages and microglia play a central role. Foamy macrophages and microglia, containing degenerated myelin, are abundantly found in active multiple sclerosis lesions. Recent studies have described an altered macrophage phenotype after myelin internalization. However, it is unclear by which mechanisms myelin affects the phenotype of macrophages and how this phenotype can influence lesion progression. Here we demonstrate, by using genome wide gene expression analysis, that myelin-phagocytosing macrophages have an enhanced expression of genes involved in migration, phagocytosis and inflammation. Interestingly, myelin internalization also induced the expression of genes involved in liver-X-receptor signaling and cholesterol efflux. In vitro validation shows that myelin-phagocytosing macrophages indeed have an increased capacity to dispose intracellular cholesterol. In addition, myelin suppresses the secretion of the pro-inflammatory mediator IL-6 by macrophages, which was mediated by activation of liver-X-receptor β. Our data show that myelin modulates the phenotype of macrophages by nuclear receptor activation, which may subsequently affect lesion progression in demyelinating diseases such as multiple sclerosis.

Topics: Animals; Cell Movement; Cells, Cultured; Cholesterol; Gene Expression Profiling; Humans; Hydrocarbons, Fluorinated; Inflammation Mediators; Interleukin-6; Lipid Metabolism; Liver X Receptors; Macrophages, Peritoneal; Mice; Mice, Knockout; Multiple Sclerosis; Myelin Sheath; Oligonucleotide Array Sequence Analysis; Orphan Nuclear Receptors; Phagocytosis; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Sulfonamides

CD4+ Th17 cells are believed to play an important role in the development of a variety of autoimmune diseases including EAE, an animal model of MS. Previously, we and others demonstrated that LXR agonists suppressed the activation of primary glial cells and blocked the development of EAE. The present studies demonstrated that the LXR agonist T0901317 suppressed IL-17A expression from splenocytes derived from Valpha2.3/Vbeta8.2 TCR transgenic mice and from MOG(35-55)-immunized C57BL/6 mice. Furthermore, in vitro treatment with IL-23 alone or in combination with MOG(35-55) induced IL-17A expression from splenocytes derived from MOG(35-55)-immunized mice, and T0901317 blocked this induction. In vitro treatment with the LXR agonist suppressed IL-23R expression by splenocytes. In addition, in vivo treatment with the LXR agonist suppressed IL-17A and IL-23R mRNA and protein expression in EAE mice. These studies suggest that LXR agonists suppress EAE, at least in part by suppressing IL-23 signaling. Recent studies indicate that the cytokines IL-21 and IL-22 are produced by Th17 cells and modulate immune responses. Our studies demonstrate that the LXR agonist T0901317 suppressed MOG(35-55)-induced expression of IL-21 and IL-22 mRNA in splenocytes derived from MOG(35-55)-immunized mice. Finally, we demonstrate that the LXR agonist T0901317 suppressed the development of EAE in an experimental paradigm involving treatment of established EAE. Collectively, these studies suggest that LXR agonists may be effective in the treatment of MS.

Topics: Animals; Autoimmunity; CD4-Positive T-Lymphocytes; Cells, Cultured; DNA-Binding Proteins; Encephalomyelitis, Autoimmune, Experimental; Hydrocarbons, Fluorinated; Immune Tolerance; Immunosuppressive Agents; Interleukin-17; Interleukin-22; Interleukin-23; Interleukins; Liver X Receptors; Mice; Mice, Inbred C57BL; Mice, Transgenic; Multiple Sclerosis; Myelin Proteins; Myelin-Associated Glycoprotein; Myelin-Oligodendrocyte Glycoprotein; Orphan Nuclear Receptors; Receptors, Cytoplasmic and Nuclear; Receptors, Interleukin; RNA, Messenger; Sulfonamides; T-Lymphocytes, Helper-Inducer

Liver X receptors (LXRalpha and LXRbeta) are nuclear transcription factors that inhibit transcription of genes of inflammation while inducing HMGCoA reductase. In this paper we demonstrate increased mRNA levels of LXRbeta in peripheral blood mononuclear cells (PBMCs) from multiple sclerosis patients with respect to other neurological patients and healthy controls (HC) (p<0.01). Agonist-induced activation of LXRs partially counteracts the anti-CD3+ anti-CD28-induced proliferation of T cells (p<0.01) and secretion of IFNgamma (p<0.001) from PBMCs of MS patients as well as of HC. Secretion of IL-4 is not affected. Our findings suggest that regulation of cholesterol metabolism not strictly related to inhibition of HMGCoA reductase can modulate activity of lymphocytes in MS.

Topics: Adolescent; Adult; Analysis of Variance; Antigens, CD; ATP Binding Cassette Transporter 1; ATP-Binding Cassette Transporters; Cell Proliferation; DNA-Binding Proteins; Enzyme Activation; Female; Gene Expression Regulation; Humans; Hydrocarbons, Fluorinated; Hydroxymethylglutaryl CoA Reductases; Interferon-gamma; Leukocytes; Liver X Receptors; Male; Middle Aged; Multiple Sclerosis; Orphan Nuclear Receptors; Receptors, Cytoplasmic and Nuclear; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Statistics, Nonparametric; Sulfonamides; T-Lymphocytes